DESCRIPTION: (Applicant's Abstract) There is evidence for a relationship between development, the biology of stress, growth retardation and substance abuse. In humans, psychosocial stressors, such as child abuse and neglect, can cause growth failure and are also risk factors for subsequent drug use and dependence. A common neurobiological substrate for stress, growth failure and drug use, is the limbic-hypothalami-pituitary-adrenal (LHPA) axis, a system that can be altered in a significant and long term manner during development (e.g., by maternal deprivation). The focus of this proposal is to understand the role of critical developmental periods which, when altered, lead to growth retardation and vulnerability to drug abuse, using the rat as an animal model. It proposes to study how the LHPA axis changes as a function of early developmental events and exposure to repeated stress, and how these factors contribute to individual differences in stress responsiveness and individual vulnerability to drug use. We shall concentrate our efforts on a particular stage of the rodent's development, the first 2 weeks of life, when activation and termination of stress can be altered in opposite directions depending on the timing of stressors. We shall focus on the hypothalamus and hippocampus, because these structures are likely to exert important neural control upon the LHPA axis, the growth hormone axis and the circuits which mediate behavioral sensitization to amphetamine and drug seeking behavior. Thus, we shall explore these issues via four interrelated sets of studies: 1) In a series of developmental studies, we shall examine the neuronal bases of the stress hyporesponsiveness (SHRP) in the rat and the mechanisms associated with the emergence into stress responsiveness; 2) We shall look at the consequences of early stress (maternal deprivation at specified times in life) on growth parameters, on the duration of the SHRP, and on stress responsiveness as an adult, focusing on related changes in the brain elements of the LHPA and the endocrine response to novelty; 3) In studies focusing on amphetamine behavior sensitization, we shall examine if the individual differences in stress responsiveness predispose to drug seeking behavior. 4) Finally, we will attempt to revert the long term negative effects of maternal deprivation by blocking the LHPA response to stress during early life. In summary, we shall study how events taking place during development may impact on growth and drug use. These studies should further our general understanding of the developmental biology of stress responsiveness and individual vulnerability to drug use and increase our knowledge of a key aspect of drug abuse biology.